Systemic toxicity in hepatic Propionyl-CoA Carboxylase deficiency

To understand the contribution of mitochondrial propionyl-CoA metabolism to cellular and systemic metabolic dysfunction, we generated inducible and tissue-specific knockout (KO) mouse models of Pcca. Adult inducible loss of Pcca results in acute metabolic decompensation resembling the inborn error.

The liver-specific loss of Pcca largely recapitulates this in a sexually dimorphic manner. Propionate and pyruvate converge in the TCA cycle as major anaplerotic substrates. Paradoxically, the simultaneous KO of Pyruvate Carboxylase (Pcx) rescues the lethality of liver-specific Pcca KO male mice.